1. Field of the Invention
The present invention relates to the treatment of ocular hypertension encountered in patients suffering from glaucoma or other ocular disorders. More particularly, this invention relates to a composition and method for effectively lowering mammalian intraocular pressure.
2. Description of the Prior Art
Increased intraocular tension is caused by a disruption of the normal mechanisms regulating the pressure within the eye of a mammal. A great deal of progress has recently been made in understanding these mechanisms. It is now well established that aqueous humor drains from the eye through a sieve-like barrier into a complex network of small vessels. Ocular hypertension is directly related to rate of secretion of aqueous humor into the eye and to outflow resistance of the drainage channels, although the mechanisms of these phenomena remain to be elucidated.
One of the diseases of the mammalian eye characterized by increased intraocular tension is glaucoma. Manifestations of glaucoma include hardening of the globe, excavation of the optic disc and restriction of the field of vision. Glaucoma causes blindness and, in Western man, indeed, is the leading cause of blindness.
The presently available methods of therapy for the treatment of glaucoma consist mainly of the administration of miotics, the adrenergic drug epinephrine, carbonic anhydrase inhibitors, and/or surgery. Surgery usually is reserved for the treatment of the less common, acute congestive form of glaucoma and for those cases of chronic open-angle glaucoma that do not respond to drug therapy. The carbonic anhydrase inhibitors seldome suffice as the sole means of therapy and are used in conjunction with moitics in the therapy of chronic glaucoma and as a preparatory measure to reduce intraocular pressure prior to surgery.
At the present, the mainstay of glaucoma therapy is the topical administration of miotics. The most commonly employed miotic is pilocarpine. This drug has certain disadvantages, namely, the need for frequent administration, usually around the clock instillation. In addition, pilocarpine causes a "pin point" pupil with associated restriction of vision. Incidentally, the loss of motility of the iris, as manifested by the "pin point" pupil, when miotics are employed is a pronounced disadvantage of all drugs presently used in the treatment of glaucoma. In addition, tachyphylaxis or tolerance to the drug is not uncommon, and increasingly stronger solutions must be used for continued therapy. Often, tolerance develops even to the uppermost dose level available.
In recent years the adrenergic drug epinephrine has been used as a valuable alternate or substitute to the miotics. It has been of especial value in the younger glaucoma patient, where the spasm of the ciliary muscle induced by miotic treatment is particularly disabling. Epinephrine is usually applied twice a day either with or without other drugs. Unfortunately, the drug has to be used in relatively high concentrations, has a mydriatic effect, and toleration of the ocular tissues to epinephrine usually is approximately two years. Epinephrine also induces undesirable side effects of congestive hyperemia of the conjunctival vessels due, principally, to its .beta. adrenoceptor agonist activity. U.S. Pat. No. 3,809,714 to Hussain et al. discloses the activity of dipivalyl epinephrine for the treatment of glaucoma; however, this particular compound also elicits a mydriatic (pupil dilation) response.
Mydriasis is particularly undesirable in the treatment of narrow-angle glaucoma since known mydriatic compounds such as epinphrine, nonpinephrine and dipivalyl epinephrine provoke occlusion of the irido-corneal angle with a resulting increased resistance to aqueous flow and a consequent rise in ocular tension in spite of a reduced aqueous flow.
Therefore, there is an outstanding need for new therapeutic agents and, indeed, new approaches which can be employed in the treatment of ocular hypertension, particularly in cases of glaucoma, without the attendant disadvantages of the presently available measures. The present invention provides a new pharmacological approach to the treatment of ocular hypertension utilizing .alpha.-methyl derivatives of epinephrine and norepinephrine that have been found to exhibit an unexpectedly high activity in reducing mammalian intraocular pressure without eliciting attendant undesirable pupillary and accommodative responses at concentrations effective in reducing intraocular pressures, and that are not substrates for monoamine oxidase and consequently are not readily destroyed after administration.
The unexpected nature of the present invention is further underscored by literature reports that such .alpha.-methyl derivatives are relatively inactive in other tissues as compared to epinephrine and norepinephrine, such as, for example, J. Pharmacol. Exp. Therap. 161:279-295 (1968); J. Pharm. Pharmac., 1969, 21, Suppl., 199S-205S; and JADA, 92:748-750 (1976). In Annals of Ophthalmology, 3, No. 3, 282 (March 1971), it is reported that the .alpha.-methyl derivatives of epinephrine and norepinephrine (dioxyephedrine and nordefrin, respectively) are inactive in lowering intraocular pressure.